Continuing Education Activity

Hemophilia encompasses a group of inherited disorders that alter blood coagulation. Classical hemophilia, also known as hemophilia A, is a hereditary hemorrhagic disorder resulting from a congenital deficit of factor VIII that manifests as protracted and excessive bleeding either spontaneously or secondary to trauma. This activity describes the cause of hemophilia A, reviews its presentation, and highlights the role of the interprofessional team in its management.

Objectives:

• Describe the etiology of hemophilia A.
• Outline the common presentation of a patient with hemophilia A.
• Review the management options available for hemophilia A.
• Explain interprofessional team strategies for improving care coordination and communication to advance the treatment of hemophilia A and improve patient outcomes.

Introduction

Hemophilia, which means love (philia) of blood (hemo), manifests with prolonged and excessive bleeding either spontaneously or after insignificant trauma. Hemophilia encompasses a group of inherited ailments that alter the body's normal blood coagulation. A hereditary hemorrhagic disorder resulting from a congenital deficit or scarcity of factor VIII, hemophilia A, which is known as classical hemophilia, manifests as protracted and excessive bleeding either spontaneously or secondary to trauma.[1][2][3]

Etiology

An X-linked, recessive hemorrhagic trait or gene induces Hemophilia A.  Hemophilia A's X-linked trait manifests as a congenital absence or decrease in plasma clotting Factor VIII, a pro-coagulation cofactor and robust initiator of thrombin that is essential for the generation of adequate amounts of fibrin to form a platelet-fibrin plug at sites of endothelial disruption. Female Hemophilia A gene carriers will transmit the gene to 50% of their male offspring, who will inherit the disorder. Female hemophilia gene carriers do not manifest symptoms of Hemophilia A but may have lower than usual quantities of Factor VIII. Male Hemophilia A patients do not transmit hemophilia to male offspring, but their female offspring will carry the hemophilia gene.[4][5][6][7]

Epidemiology

Hemophilia A is the most common X-linked hereditary disorder of hemostasis; it occurs in one out of 5000 males and accounts for 80% of hemophilia cases. Hemophilia A occurs in more than 400000 males worldwide, many of whom remain undiagnosed in the developing world.

Pathophysiology

When the vascular endothelium sustains an injury, the hemostatic process initiates the coagulation cascade to restore vascular integrity and prevent further bleeding. Platelet activation occurs at the site of vascular rupture, initiating promulgation of clotting factors and fibrin formation, resulting in a platelet-fibrin plug to inhibit further bleeding. Factor VIII, the deficit of which causes hemophilia A, provides essential enhancement of thrombin generation and promulgation of fibrin formation to inhibit further bleeding. Factor VIII adheres to von Willebrand factor to protect it from proteolytic degradation. Bleeding in hemophilia results from defective fibrin stabilization secondary to inadequate fibrin generation, which results in a failure of secondary hemostasis. Insufficient thrombin in the coagulation cascade results in a deficiency of fibrin.

History and Physical

Severe hemophilia often manifests in the first months of life, whereas mild or moderate hemophilia will present later in childhood or adolescence, often incidentally or following trauma. In two-thirds of cases, confirmation of the hemophilia diagnosis occurs shortly after the delivery of an affected son to a mother who carries the susceptible gene. In spontaneous mutation scenarios that occur in one-third of cases, hemophilia A diagnostic confirmation proceeds after bleeding symptoms occur spontaneously or after insignificant trauma. Characteristic hemophilia bleeding symptoms can manifest as spontaneous intracranial bleeding in neonates, excessive postoperative bleeding after circumcision, atraumatic painful hemarthrosis, inexplicable bruising when the infant begins crawling or walking, and inordinate musculocutaneous hemorrhage, either spontaneously or after intramuscular vaccination. Frequent falls or impacts from furniture while learning to ambulate can induce extensive soft tissue contusions and hemorrhage that can mimic the appearance of child abuse in the young hemophiliac. Hemarthrosis manifests as the most common hemorrhagic symptom in adolescents and adults. Recurrent hemarthrosis eventually causes erosion of joint cartilage and results in the painful Charcot joints of hemophilic arthropathy. Intracranial hemorrhage represents the most immediate life-threatening manifestation of hemophilia A with the potential for chronic neurological disability and long-term neurological sequelae.

Evaluation

Diagnostic evaluation for hemophilia occurs in the setting of a known family history, excessive bleeding out of proportion to the traumatic injury, or abnormally activated partial thromboplastin time. Normal hemogram and prothrombin time in the setting of elevated activated partial thromboplastin time heightens the suspicion of hemophilia and should prompt factor VIII and IX determination. Determining residual plasma concentration of factor VIII represents the keystone of diagnosis, classification, and treatment of hemophilia A as therapy and prognosis will vary depending on factor VIII deficiency. Most hemophilia A patients have a prolonged activated partial thromboplastin time; however, a normal result does not rule out mild hemophilia. Hemorrhage severity in hemophilia A correlates with scarcity of factor VIII. Factor VIII concentration is expressed in international units (IU); 1 IU is the concentration of factor VIII in 1 mL of pooled plasma or percentages of normal pooled plasma with normal levels ranging between 50% to 150%. Severe Hemophilia A will have no measurable factor VIII, less than 0.01 IU/mL or less than 1%, and will bleed spontaneously. Moderate or mild hemophilia, 0.02 to 0.05 IU/mL (2% to 5%) or 0.06 IU/mL to 0.40 IU/mL (6% to 40%), respectively, will bleed excessively after relatively insignificant trauma.

Treatment / Management

Administration of recombinant factor VIII replacement for the treatment of acute bleeding in severe hemophilia A patients should occur promptly with initiation before completion of the patient assessment. Calculation of factor VIII replacement for bleeding in severe hemophilia A is[8][9][10]:

• Dose of factor VIII = percentage desired of factor x bodyweight (kg) x 0.5

For severe, life-threatening hemorrhage, administer factor VIII to achieve a 100% desired factor VIII level; for mild to moderate hemorrhage, administer factor VIII to achieve a 30% to 50% desired factor VIII level. Accounting for the hemophilia A patient's native factor VIII levels should be factored into factor VIII repletion if known. The combination of effective blood product screening with viral inactivation protocols and recombinant production of Factor VIII has enhanced factor VIII replacement products' safety from viral transmission, such as HIV and hepatitis C.

Other pharmaceutical adjuvant therapies for hemophilia A-induced bleeding include desmopressin, tranexamic acid, epsilon aminocaproic acid, and management of factor VIII inhibitors. Intravenous, subcutaneous, or intranasal desmopressin (DDAVP) has utility for the treatment of bleeding in mild to moderate hemophilia A patients by triggering the release of complexes von Willebrand's factor and factor VIII from vascular endothelial cells.

Periodic, prophylactic Factor VIII concentrates infusions for patients with severe Hemophilia A have benefits in preventing spontaneous bleeding. The intent of factor VIII prophylaxis aims to modify severe hemophilia to a milder form by keeping the nadir level of factors more than 1% of normal. The World Federation of Hemophilia recommends factor VIII prophylaxis initiation in hemophiliac children after their first or second episode of hemarthrosis to prevent joint destruction and preserve musculoskeletal function. Mild and moderate hemophilia A patients receive factor VIII concentrates or desmopressin to prevent hemorrhage in anticipation of trauma or surgery.[11][12]

Differential Diagnosis

• Acquired hemophilia

• Ehlers-Danlos syndrome

• Factor XI deficiency

• Glanzmann thrombasthenia

• Haemophilia C

• Haemophilia type B

• Physical child abuse

• Platelet disorders

• Von Willebrand disease

Pearls and Other Issues

Defects in the binding of factor VIII and von Willebrand factor, characterizing type 2N or “Normandy type” von Willebrand disease, will manifest like hemophilia-induced bleeding. Still, unlike hemophilia, inherited manifestation occurs in an autosomal pattern, thereby also affecting female patients. Establishing the diagnosis of type 2N von Willebrand disease utilizes molecular genetic testing.

Many severe hemophilia A patients, nearly 30%, develop alloantibodies against administered factor VIII. Inhibitor development represents a major complication and challenge in hemophilia treatment because these alloantibodies inactivate the procoagulant effect of infused factor VIII, thereby inhibiting the response to factor VIII replacement.

Enhancing Healthcare Team Outcomes

Hemophilia A management is best by an interprofessional team that includes hematology nurses. Once the diagnosis is confirmed based on plasma factor VIII levels, patient and family referral for genetic screening and counseling for factor VIII gene mutation analysis to establish carrier status.

The outlook for most patients with hemophilia A is guarded. Repeated transfusions of blood products and related factors are not benign events. Additionally, these patients are prone to bleeding, which can be life-threatening.

The pharmacist should perform a thorough medication check, looking for any agents that might precipitate bleeding, as well as verifying dosing of clotting factors and any other medications (eg, pain control.). Nurses can provide patient counseling, report concerns to the managing clinician, and monitor patient progress and status. These interprofessional examples demonstrate how this approach can optimize patient outcomes. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

López Fernández MF. Limitations of prophylactic treatment in patients with hemophilia. Blood Coagul Fibrinolysis. 2019 Sep;30(1S Suppl 1):S22-S24. [PubMed: 31157677]

2.

Mahlangu J. Emicizumab for the prevention of bleeds in hemophilia A. Expert Opin Biol Ther. 2019 Aug;19(8):753-761. [PubMed: 31150297]

3.

Oldenburg J, Hay CRM, Jiménez-Yuste V, Peyvandi F, Schved JF, Szamosi J, Winding B, Lethagen S. Design of a prospective observational study on the effectiveness and real-world usage of recombinant factor VIII Fc (rFVIIIFc) compared with conventional products in haemophilia A: the A-SURE study. BMJ Open. 2019 May 30;9(5):e028012. [PMC free article: PMC6549707] [PubMed: 31152037]

4.

Ulrich-Merzenich G, Hausen A, Zeitler H, Goldmann G, Oldenburg J, Pavlova A. The role of variant alleles of the mannose-binding lectin in the inhibitor development in severe hemophilia A. Thromb Res. 2019 Jul;179:140-146. [PubMed: 31141731]

5.

Tegenge MA, Mahmood I, Forshee R. Clinical Pharmacology Review of Plasma-derived and Recombinant Protein Products: CBER Experience and Perspectives on Model-Informed Drug Development. Haemophilia. 2019 Jul;25(4):e240-e246. [PubMed: 31131515]

6.

Miesbach W, O'Mahony B, Key NS, Makris M. How to discuss gene therapy for haemophilia? A patient and physician perspective. Haemophilia. 2019 Jul;25(4):545-557. [PMC free article: PMC6852207] [PubMed: 31115117]

7.

Schep SJ, Boes M, Schutgens REG, van Vulpen LFD. An update on the 'danger theory' in inhibitor development in hemophilia A. Expert Rev Hematol. 2019 May;12(5):335-344. [PubMed: 30951401]

8.

Samuelson Bannow B, Recht M, Négrier C, Hermans C, Berntorp E, Eichler H, Mancuso ME, Klamroth R, O'Hara J, Santagostino E, Matsushita T, Kessler C. Factor VIII: Long-established role in haemophilia A and emerging evidence beyond haemostasis. Blood Rev. 2019 May;35:43-50. [PubMed: 30922616]

9.

Top O, Geisen U, Decker EL, Reski R. Critical Evaluation of Strategies for the Production of Blood Coagulation Factors in Plant-Based Systems. Front Plant Sci. 2019;10:261. [PMC free article: PMC6417376] [PubMed: 30899272]

10.

Preijers T, Schütte LM, Kruip MJHA, Cnossen MH, Leebeek FWG, van Hest RM, Mathôt RAA. Strategies for Individualized Dosing of Clotting Factor Concentrates and Desmopressin in Hemophilia A and B. Ther Drug Monit. 2019 Apr;41(2):192-212. [PubMed: 30883513]

11.

Lasne D, Pouplard C, Nougier C, Eschwege V, Le Cam Duchez V, Proulle V, Smahi M, Harzallah I, Voisin S, Toulon P, Sobas F, Galinat H, Flaujac C, Ternisien C, Jeanpierre E., groupe d'études de la biologie des maladies hémorragiques du Groupe français d'études de l'hémostase et la thrombose. [Factor VIII assays in treated hemophilia A patients]. Ann Biol Clin (Paris). 2019 Feb 01;77(1):53-65. [PubMed: 30799298]

12.

Emicizumab for haemophilia A. Aust Prescr. 2019 Feb;42(1):42. [PMC free article: PMC6370604] [PubMed: 30765913]

Disclosure: Philip Salen declares no relevant financial relationships with ineligible companies.

Disclosure: Hani Babiker declares no relevant financial relationships with ineligible companies.